Alkamine esters of 4-alkylaminothiolbenzoic acids



Patent'ed Aug. 26,1952

'ALKIAMIN-E Esrsas F 4-ALKYLAMIno- 'rmomenzorc ACIDS Raymond 0. Clinton, Delmar, N. Y., assignor to Sterling Drug 1110., New York, N. Y., a corpora- ,w

tion ofDelaware" No Drawing. Application February 12, 1949; I 1 .Serial No. 76,190 I r This invention relatesto basic thiol esters.

salts thereof, and toprocesses for preparing the same. It more particularly relates to alkamine esters of -alkylaminothiolbenzoic acid, and to water-soluble acid addition saltsi of the same.

The basic thiol esters; of this invention have i the general formula.

where R is an a lower alkylenef group, and NB, is a lower aliphatictertiary amino group. v These esters, preferably in the form of their water-soluble acid addition salts, have been found to e:;hibit valu able pharmacological properties, in particular,

local anesthetic properties.

In the foregoing general formula, the alkyl or hydroxyalkyl group, represented by R, preferably has from 3 to 7 carbon atoms, representative and 5,1,.

illustrative examples" being n-propyl, isopropyl, n-butyl, 2-amy1, n-heptyl, 2-hydroxy- 1-p'ropyl,

'B-hydroxyhexyl, and the like. The lower alkylene group, represented hereinabove as X, preferably has from 2 to 4 carbon atoms, including such --olmen om) 13 cl i s; (01. zoo-493.4)

alkyl or hydroxyalkyl group, x is "I he basic thiol esters ofmy invention'can be thelike. The lower aliphatic tertiaryamino group, shown above as NB, comprehends lower dialkylamin o groups illustrated by examples such as dimethylamino, diethylamino, ethylmethylamino, di-n-butylamino, and the like; and, lower saturated N-heteromonocyclicgroups havingj to 6 ring, atoms. illustrated by examples, such 1 as 1- piperidyl, ;.2 methyl l-piperidyl, 3 methyl-- 1' piperidyl, 2,6 dimethyl 1 piperidyl, 1 pyrrolidyl, 2 methyl 1. pyrrolidyl, 4 morpholinyl, and the like. In other words, BNH

designatesa lower aliphatic secondary-amine as illustratedby diethylamine, di-n-butylamine, 4- rnethylpiperidine, morpholine, and the like.

\ Specificillustrations of the basi thiol esters of myinventionfollow:

(1) l idiethylaminoethyl 4- (Z-butyl) aminothiolbenzoate V I (2) 3-(2-methy1-1-pyrro1idyl)propyl -n-propyl- It i i l n ea e (3-) 4-dimethylaminobutyl 4-n-hexy laminothiolbenzoate y 4) 2-(2,6-dimethyl-1-piperidyl)ethyl i -(z llidroxy-l-propyl) aminothiolbenzoate prepared by various methods. .The'methodpreferred in practicing my invention involvesreduc tive alkylaticn of a tertiary-aminoalkyl-amino thiolbenzoate of the formula where X and NB have the meanings designated hereinabove, with an alkanal or hydroxyalkanal. An illustration is the formation of Z-diethylaminoethyl 4 n-propylaminothiolbenzoate by treating the corresponding alkamine 4-aminothiolbenzoate with propionaldehyde in a reducing medium. Illustrative of this method utilizing a hydroxyalkane carbonyl compound is 'thefiQi' mation of 3- (1-piperidyl)propyl 4;}(3-hydrdxyyll1- .hutyleimino) thiolbenzoalte by treating B llpiperi'dyl) propyl 4; amino thiolbenzoate, with; fhjydroxy-l-butanal in a reducing medium, suchfas zinc dust and acetic acid, iron and acetic.jauid,

, or a catalytic reducing medium usinglasulfur insensitive .catayst, e. g. molybdenum. sulfide- Another style of synthesis of the thiol esfters ofmyflinvention is the direetelkylation;.ofg.p-

Another mode of synthesis of the thiol ester hydrohalides where R is alkyl is based on the reaction between a tertiary-aminoalkanethiol -"oi the formula, BNXSH, and a 4-alkylaminebenzoyl halide hydrohalide of the formula",

4-RNHCGHiCOY-HY where R is a lower alkyl group and Y is halogen,

preferably C1 or Br. Illustrative'of'this synthesis is the formation of 3-diethylaminopropy1 l n butylaminothiolbenzoate dihydrochlori'deiwfrom,

3-diethylaminopropanethiol and l-n-butylaminohenzoyl chloricle hydrochloride. However, the foregoing, reductive alkylatiorrmethod was found preferable tothisprocedure in practicing my;invention,. 'since purificationwa's more easily effected.

Thetertiary 1 aminoalkyl-d-aminothiolbenzoatesfisignated=hereinabove=as i! witlrXandNB. having theabove givenmeanings,

are readily prepared by the, following seriesof're- PQ 'I I. 11.1,;-

l III QiEach oi the intermediate products designated asia,b,:c, d and e as well astheprocesses of pregenerally knownin the art.

Thealkamine thiol esters of my'inve'ntionare therapeutically active uwhether. employed as the free bases, whichsarethe active compounds, or as their saltslwith relatively non toxic organic or in- .Qrganic acids. In practicing my invention I found it convenient to; isolate the basic esters-as their hydrochlori'des'; citrates, 'or phosphates. -'-How- "ever; fother acid; addition salts '"are within the scopeo'fmyinvention. Such additional saltsiinclude the dihydrobromide, *sulfate, 'sulfamate, tartrate, succinate, udiacetate, dibenzoate, dioleate, and the like. v,

*The following examples winfurther illustrate flowing preparation fntoeanolig.- .q A mixture' of Tlofgj."of2-methylpip'er1dine; 36.8 g. ,of trimethylene "chlorohydrin, i800 "ml."of';ab-

fsolute alcohbl and 303:of sodiuni-iodide'or potas slum iodide,-was refluxed-withstirringfor twentyring them .(designated.asl. I V) are 4 four hours. The stirred reaction mixture, after cooling, was treated with a solution of g. 01 sodium in 1500 ml. of absolute alcohol, filtered, and the filtercake washed Well with ether. The filtrate was distilled at atmospheric pressure, iiwith, mechanicai stirririg, twelve-inch Vigreux columnto a head temperatureo'f 122 C., .reserving the fraction of B. P. 105-122 C. for recovery of z-methylpiperidine. The still residue t-wasgdiluted witn'about three volumes of ether, Ifilt'eredgand distilled, first at atmospheric pres- .sure and then in vacuo. Redistillation gave 582 g. yield ,basedgbntrimethylene chlorohydrin oi-'flzqtgyild lbased. on recovered 2-methylpiperldine) of '3 (2-inethyl-1-piperidyl) propanal, B. P. :l+l081'C'. -at.10-11 mm.; 11 1.4769.

In a similar manner using morpholine in place of 2=methylpiperidine 3- l-morpholinyl) propanol was prepared in 92% yield (twice distilled), B. P. 109 -111 C. at78 mm, 5 1.4745;,and 'using piperidi-ne, 3-(l piperidyl) =propanol "was prepared in 9-3-% yield '1 (twice *distil'led B1 1 3 .5-95C."at 9*mm.,*-1i *1;47:55. 5

Tertiary-aminoe'thafnols were convenientlyprepared-"by reacting the appropriate secondary amine-with" ethylene oxide in' boiling methanol by a method similar to that elf-Pollard (JL AQ'Cx'S. 57, 1988 (1935)). For example, the reaction between 2-methylpiperidi-ne and ethylene oxide yielded 86% of 2-(z-methyl l' piperidyl) ethanol aea colorless,.slightly viscous oil, B..P. :98-100" C. at-l5 ."mm" 1 14782. A;s'ample'.redistilledifor analysis;had a.B..-P. of .87.'0 ;a't 8 r5 .1 88. v:2 .(2 rne'thyl-ll p'yrrolidylbethariolB. IP. .72 I :8 .and 153 .1.4;683, was obtained u sing ans same gprocefiure .wi'thi'i emethyllpyrr'olidine .as the secondary amine.

a Tertiaw aminodlkiijkchlorides -Theseintermediatemasimalkyl chloridesrcanfbe ,prepared by; any known method. .lioimdnt iconvenientgtotreat the foregoing; described tertiaryeminoalkancls with thionyl chloride :in the usual ,manner. Thus,-when-thebasic;alkanol-was 2+(2- methyl-l piperidyl);ethanol the resulting. 01110- ride, obtainedvinf98.% yield,-was.2-(.z-methylelpiperidyl) ethyl chloride hydrochloride, white needles from isopropanol, M. P. 184-185 C. 2-(2 methyl-l-piperidyl)ethyl chloride, which was lib- .erated fromthehydrochloride by sodiumhydroxjideals arcoloiilesmmobile 011,3. necaloaorams Other ,alkamine, chlorides preparefd by treating the corresponding basic. alkanol with. ,thionyl "chloridejin the usual mannerwere 2-.(2-methyl- .1-pyrrolidyl) ethylchloride hydrochloride, M. P; rev-188 c. and 3 (2-methyle1 piperidyhpropyl chloride hydrochloride, M. ,P. v1772-4782" .G. (shinyplatesfromisopropanol-ether)..

'iT-ertiary-aminodlkanethiols Thenew .basic thiols used in theinstantrapplication .were .prepared by .methods previously describedlClinton et,.-al.,- J. A. C; S. 70, .950 (1948).). .Forexample, reaction betweenZ-(Z- methyl-l-piperidyl) ethyl chloride aandv :thiourea in absolute ethanol. gave a .94%;-yield gof IZ-(QZ- methyl-l-piperidyl) ethylisothiouronium chloride hydrochloride, white needles from absolute ethanol, M. P. 226-227 C. The latter compound, on hydrolysis, gav e .a 57% yieldof .Z-(Z-methyl-lpiperidyDethanethiol, *colorless liquid, B. P. ens-910 c. at 14 mm., 1 1.4974. 2-(2 methyl l 'pyrrolidyD'ethyl chloride. .hydrochloride gave with thiourea in absolute eth esteem dyllethylisothiouronium chloride: hydrochloride, white needles from'isopropanoL'M. P; 205-208 C. Fromthis isothiouronium salt was obtained a 44% yield of 2-(Z methyI-LpyrrQlidyI)ethane thiol as a colorless mobile liquid, B. P."7411- 745" e rn mm., n 1.4898.

3 4-morpho1'inyl) propyl Chloride hydrochloride (Adamsand Whitmore, J. 'A.' C. S.- 67, 735 (1915) and 'thiourea in absolute ethanol gave a 95% yield of 3-(4-morpholinyl)propylisothiouremum chloride 'hydrochloridejwhite needles rrom absblute ethanol, .P. 218-220 o. By the The'se" basic "esters werdprepared by reacting' -j-nit'robenzoy'l chloride with the appropriate tertiary-aminoalkanethiol'in coldbenzene EAlbertson andClinton, A. C. S. 67, 1222 (1945)] Orin a. "chloroform-water-sodium bicarbonate admixtii're' (cantonct fal., J. A; c: s. 70, 950 (1948));2 These esters; in the form of their hydroohlorides, have the following general formula .7 5 12.11

pared as hereinabove described have the general" formul u Ifgfl where and NB have, the following meanings;

' i o Phosphaten NB M. P., C. Pu so" 2 N(GH;)1 I 187-1892 3 N(C:H5)2- 209.8-21013 4 N(O;Hs)2 1992-2003 2 NC4l-I8O 1 207-208 3 NC4H5O 1 129-1355 2 NCsHw a 204-206 3 NO5H10 3 210-2112 2 N05111: 196.7-1973 3 NGsHu 223.42Z4.0 5

( N(CzH5)z 147-151 1 i-morpholinyl.

3 White leaflets from a large volume of benzene or blunt prisms from absolute ethanol.

3 l-piperidyl.

4 Long white needles irom petroleum ether.

5 Base crystallized from dilute etnanolas an unstable hydrate, M. P. 78-80 0., and from benzene-petroleum ether in the anhydrous form, M. P. 60-61 O.

$1 lsteported M. 1a 187* (dec.) (RenshawetalfJ; 'Alo. s. "so, 1765 193 I i-morpholinyl. a The base crystallized in pale yellow needles from dllute ethanol, Hts-1 1.62.564.0 C. 4 Y

1piperi lyl.

2-m'ethy1-l-piperi(ly1." Iz-methyl-l-pyrrolidyl.- 7 The base melted at 53-55 C. (from petroleum ether). ,Tertiary-aminoaZIcg l;.4-amimthiolbenzoates These esters were prepared byi-eduction of the corresponding 4 nitrothio lbenzoates described hereinaboye. The reduction was preferably carried out We method similar to that of West J. 'AJC. SL127, 495 uezsyysmce the r rous sulfate-ammoniamethod (Clinton et a'L, J.'A. C'. s; to, 950 (1948 o'fi'eredndeyident ad-f vantages in this case? Certain ofthefresultirig tertiary-aminoallryl 4-aminothiolben'zoates were obtained crystalline. These basic" esters pre- 2-methyH-pipcridyl. f h i i Large white feathery needles from petroleum ether.

5 Flavian ate, with a base to flavianic acid ratio of 3 to 2.

9 NB-X- or the tertiary-aminoa1kyl amiuo-2-pentyl. a.

ry-lawma er btltylemiepih benzoates.

The tertiaryeaminoalky1 ..4alkylaminothiolbenzoates of my invention were prepared either by alkylation of the corresponding basic' l-amino compounds or directly-from a 4-;alkylaminobenzoyl chloride hydrochloride and a dialkylaminoalkanethiol. The preferred method, wherein purification was more easily efiected, was that of reductively alkylating the corresponding alkamine 4-aminothiolbenzoates. -with an aldehyde in the presence of zinc dustand acetic acid. The basic esters thus obtained were, in; most cases, mobile, pale yellow oils which readily yielded crystalline salts. Exemplary of this pro cedure is the following preparation of Z-diethyI- aminoethyl 4-n-butylaminothiolbenzoate.

zoata-To a refluxing, stirred mixture of 20.0'g; of 2-diethylaminoethy1 4-aminothiolbenzoate, 20.6 g. of zinc dust (4 mole proportion),'.19.5 g. of glacial acetic acid (4.1 mole proportionland ml. of benzene there was added dropwise during twenty minutes a solution of 6.9 g., of nebutyraldehyde (1.2 mole proportion) in 20 ml. of benzene. Refluxing and stirring were con tinued for an additional onehour. The mixture was filtered While hot, and the filter cake "was washed thoroughly, with hot benzene and with dilute acetic acid. The filtrate wasmade basic to litmus with dilute sodium hydroxide solution,

clarified by re-filtration, and the benzene layer separated. The aqueous layer was twice reextracted with benzene, the combined benzene, extracts were washed once with water, and dried,

overDrierite. Evaporation in vacuo yielded, as, a mobile yellow oil, 23.0. g. of Z-die'thylamino} ethyl 4-n-butylaminothiolbenzoate.

Citffate.A solution of 193g. of the basef Z-diethylarhinoethyl 4-n -butylarninothiol1- benzoate, and 13.2 g. of citric acid monohydrate group here is 5-diethylin"; 10.0 ml. of; warm? absolutev alcoholv wasv cooled and diluted to turbidity with ethyl acetate; On.- scratching and further cooling the citrate crystallized. Two recrystallizations from absolute alcohol-ethyl acetate gave pure material, Z-diethylaminoethyl 4-n-butylaminothiolbenzoate citrate, M. P. 149.5150.5 C. (corn).

Dihydro-chlorida-A solution of 2-diethylaminoethyl 4-n-butylaminothiolbenzoate in ethyl acetate was treated with an excess of ethereal hydrogen chloride- The-solvents were decanted from the precipitated gum, and the latter was crystallized from isopropanol in the presence of a small amount of ethereal hydrogen chloride. Recrystallization fromisopropano1 (HCl present) gave whiteprisms of Z-diethylaminoethyl 4-hbutylaminothiolbenzoate. dihydrochloride, M. P. 142.6-14516C; (corn).

Other tertiary-aminoalkyl 4en-butylaminothiolbenzoates' prepared. according to the above described procedure using'n-butyraldehyde and the appropriate alkamine e-aminothiolbenzoate are those having the general formula ooswHmNB-moi where n and NB have the following meanings:

n, NB. LLB, 9G. I

2 N(CH:)2 157-1615 2; N(CZH)2 142.671.45.6f

' I NKCZHQ: 15415-156 3-. NCZHiO mas-127.2 g NC HM zone-203.4 3" NCiH'it 18648851 2: NcsH z 112.5?124l5 3.: N05131:", 170.8-17314- from benzene petroleum other).

"Other alkamine 4-alkylamihothioibenzoates prepared. according to the foregoing described reductive alkylation method include the followme:-

*2-diethyl'ami noethyl 4-n-propylaminothiolbenzoate, from the correspon'ding-aminoesterand propional'dehyde; the picrate crystallized from. alcohol in canary yellowneedles, M. P. 1295- 13 1.5-' C'." Z-di'ethylaminoethyl -n-propylaminothiolbenzoate dihydrochloride, crystallized from absolute alcohol-acetone-ethyl acetate in massive; pale yellow prisms, melts at.1'52.4-153'.5C.

Z-diethylaminoethyl' 4-n-heptylaminothiolbenzo'ate citrate, preparedfrom thebase (reductive alkylation with n-heptaldehyde) and citric acid inonohydrate in acetone, crystallized. inrosets .of tiny White needles, from absolute alcoholrethyl. acetate, M. P. 123-124? C. ('de.c.).

.Breparation of my compoundswhere R.is hyd'roxylalkylcanbe effected by the above-described reductive alkylationmethod. In sucha preparaor? 1%e prisms from absolute ethanokpetrolewn plaryroii.suchan.alkamineeehydroxyalkylaminoa thiolbenzoate prepared. by, the; above.-descrihed reductive alkylation methodz. r

2; a :dtethulaminoethyl 4...- (.5 n .-hudro:cyomgl'- amino) thiolbeneoater-Ihis.preparation .was car? ried; out; according; to the. aboye+described pro cedure; used. in preparing; 2..-diethy1aminoethyl; 4.-nebutylaminothiolbenzoatesave: the following reactants, and: quantities ,thereoi. .were: used: 25.2 g of. Zediethylaminoethyl.4eaminothio1benzoate; 26.2 g. of: zinc dust, 24 d.- g; .oielacialacetic; acid; 150. m1; of; benzene, and; 12.4; g. of: 5.-hy,droXy;- .pentana'l; in 20, m1., of; benzene. Refluxing and; stirring:werezcontinued ion-two. hours: afteiradditionotthe; 5.-hydigoxynentanal was completed;

Removal. of. the; benzene. from the; dried. benzene;

extraotsyieldeda solid.which.whenrrecrystallized; from; benzeneen-hexane; formed.- large. white. prisms. of. zrdiethylaminoethyl; 4.:(5-hyd-roxyrne amylaminoizt-hiolbenzoate, M. R. '72,3-73:6 C. The; pjcrater. formed. tiny; orangeeyellow needles.- from alcohol, M. P. 965.648.29 6.. 2-:- diethylaminoethyl 4 -(5 nhydroxyamylamino)'thiolbenzoate phosphate; prepared-by admixture or equimolecularramountsgofrthe basic esterandwphosphoric acid; inaacetone; .crystallizediirom: alcoholeacetono in: resets of: white; cottony needles;., M. 1%.; 163.;69-

Imthe iforegoingidescribed. reductive; alkylation. procedure; other; reaction. SDIVGIltSf; such; asztolue ene, xylene; chloroform, butyl ether; dioxane-,-,and* the like, can beiusedaina placer-of benzene; however. I found benzene to give the best results. The mole ratios of reactants as specified in the above preparation are optimum, however said ratios can be varied somewhat by increasing the amounts of reactants other than the 4-amino compound. The aldehyde-addition and reflux times are variable, i. e., With-tolueneshorter reflux time suffices because of. the higher temperature of the reaction medium.

My compound whereR isalkylalso can be prepared by reacting: an alkamine, thiol', with a 4-alkylaminobenzoyl halide hydrohalide. The

'fo1lowing preparation" is illustrative of this method:

Z-diethyZaminOethyZ' eteneamyl'aminothiolbenzoate.-Reductive-.alkylation, of ethyl 4-aminobenzoate with nevaleraldehydegavera yield of ethyl i-amylaminobenz'oate', whitepris'ms from n-hexane, M. P}, 54.0-55.00': Saponification of the ester with aqueous-ethanolic sodium; hydroxide solution gave a; 99% yield of i-n-amylaminobenzoic': acid, whiteneedlesfrom dilute-ethanol, M. P. 135.5-136.5 C. This acid was converted to the chloride hydrochloride either by the. phosphorous pentachloride procedure of Grai" and Langner (J. prakt. Chem., 148, 161. (1937) or the thionyl chloride procedure of. Mn-d'zhoyan [J'. Gen. Chem. '(U'; S. S. R.), 16; 1033 (1946) (Chem. Abstr;, 4'1, 2'73?- (19475 l;-the'resulting' 4-n-amylaminobenzoyl chloridehydrochloridewas; used without purification because of instability. Cone densationwith; Z-diethylaminoethanethiol inbenzene ave after: several purificationeby CHIS! tallization and conversion to the base, a 45% yield of: .2,-diethylaminoethy1.; 4,-neamylamino thiolbenzoate asa pale yeilowoil: The picrate formed pale orange: needles from; ethanol, B. 120.2121.2?C.,(corn).

Thissame basic ester, 2.-dieth-ylaminoethyl l-n-amylaminothiolbenzoate, was prepared according to the above described reductive alkylation method from 2-diethylaminoethyl i-aminothiolbenzoate and n-valeraldehyde in 90% yield.

I claim: 1. A member of the group consisting of a basic thiol ester of the formula 7 where R is a radical containing 3 to 7 carbon atoms selected from the group consisting of alkyl and hydroxyalkyl groups, X is a lower alkylene group having 2 to 4 carbon atoms and NB is a member of the group consisting of di-(lower alkyl) amino, each lower alkyl radical having 1 to 4 carbon atoms, and saturated N -heteromonocyclic groups having 5-6 ring atoms, and acid addition salts thereof.

2. An acid addition salt of a basic thiol ester of the formula where R is a lower alkyl group having 3 to 7 carbon atoms, the lower alkyl radicals each have 1 to 4 carbon atoms and X is a lower alkylene group having 2 to 4 carbon atoms.

3. An acid addition salt of a basic thiol ester of the formula where R is a lower alkyl group having 3 to 7 carbon atoms, X is a lower alkylene group having 2 to 4 carbon atoms and N13 is a lower saturated N-heteromonocyclic group having 5 to 6. ring atoms.

4. An acid addition salt of a basic thiol ester of the formula where the lower alkyl radicals each have 1 to 4 carbon atoms.

5. An acid addition salt of a basic thiol ester of the formula where the lower alkyl radicals each have 1 to 4 carbon atoms.

6. An acid addition salt of a basic thiol ester of the formula where NB is a lower saturated N-heteromonocyclic group having 5 to 6 ring atoms.

7. An acid addition salt of a basic thiol ester of the formula where NB is a lower saturated N-heteromonocyclic group having 5 to 6 ring atoms.

8. An acid addition salt of Z-diethylaminoethyl 4-n-butylaminothiolbenzoate.

9. An acid addition salt of 3-diethylaminopropyl 4-n-butylaminothiolbenzoate.

10. An acid addition salt of 2-dimethylaminoethyl 4-n-butylaminothiolbenzoate.

11. An acid addition salt of 2-(2-methyl-1 I piperidyDethyl 4-n-butylaminothiolbenzoate.

12. An acid addition salt of 3-(1-piperidy1) propyl 4-n-butylaminothiolbenzoate.

13. 2-diethylaminoethy1 i-n-butylaminothiolbenozate dihydrochloride.

RAYMOND O. CLINTON.

REFERENCES CITED OTHER REFERENCES Hansen: J. Am. Chem. 800., vol. 55, pp. 2872- 2874 (1933). 

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC THIOL ESTER OF THE FORMULA 